1. Gluconeogenesis

2. Gluoconeogenesis • Is the formation of glucose from non-carbohydrate sources e.g lactic acid ,amino acids , glycerols and propionate. • Site: liver and kidney.

3. Cont. • Liver and kidney contains all enzymes of glconeogenesis. • It does not occur in skeletal muscles due to deficiency of glucose -6-p • It does not occur in heart muscle,smooth musacles, and dipose tissues due to deficiency of fructose 1-6 dip.

4. Importance • Glucose is the only source of energy: • 1. nervous system • 2.Skeletal system • Glucose is required : • 1. Adipose tissues: as a source of glycerol • 2.Mammary gland:as a source of lacotse

5. glycolysis gluconeogenesis sugar (re)new make/ create gluco neo genesis glucose pyruvate lactate

6. Topics: Gluconeogenesis • Principles, substrates & relationship to glycolysis • Bypass of irreversible steps in glycolysis • Link between liver gluconeogenesis and muscle/RBC/brain glycolysis; the Cori and Alanine cycles

7. Gluconeogenesis • Occurs in all animals, plants, fungi and microbes • Occurs largely in the liver; some in renal cortex • Of 10 enzymatic steps, 7 are reversals of glycolytic reactions

8. Carbohydrate synthesis from simple precursors

9. Metabolites feed into gluconeogenesis at various points main path

10. All AA can feed into gluconeogenesis except leucine andlysine

11. TCA intermediates are gluconeogenic;funnel through oxaloacetate

12. Bypass of irreversible steps in glycolysis

13. Irreversible glycolytic stepsbypassed glycolysis gluconeogenesis by Glucose-6-phosphatase by Fructose 1,6-bisphosphatase (FBP-1) by Pyruvate Carboxylase & Phosphoenolpyruvate carboxykinase (PEPCK) • Hexokinase (hexK) • Phosphofructokinase-1 (PFK-1) • Pyruvate kinase (PyrK) These 3 key enzymes

14. Pyruvate can go “up” or “down” depending upon energy needs

15. First bypass step is generation of PEP from pyruvate via oxaloacetate • *Note: • In order to cross the mito membrane, oxaloacetate must: • Be reduced to malate • Go through the malate shuttle • Be reoxidized to oxaloacetate

16. Addition of CO2 to pyruvate to form oxaloacetate • Hydrolysis of ATP

17. Decarboxylation and phosphorylation to PEP

18. 2nd & 3rd bypass steps are near the end of gluconeogenesis(“top” of glycolysis) Regulation of FBP-1 by AMP and F2,6P

19. Dephosphorylation of G6P,3rd bypass reaction

20. Glucose 6-phosphatase removes the phosphate to liberate free glucose G6Pase glucose-6-P + H2O  glucose + Pi • This is primarily a function of the liver to buffer blood glucose levels • G6Pase is NOT present in brain and muscle! (Gluconeogenesis does not occur in these tissues)

21. cost Gluconeogenesis is energetically expensive to cells (hepatocytes)

22. Note that both Glycolysis and Gluconeogenesis are energetically favorable under physiological conditions and therefore both ~ irreversible processes Glycolysis DG[phys] = -63 kJ/mol Gluconeogenesis DG[phys] = -16 kJ/mol

23. Liver is the major source of blood glucose from GN Is the primary gluconeogenic organ Produces glucose for export to brain, muscle, RBC’s Uses many small metabolites and fatty acids to feed GN Liver function is highly sensitive to insulin & glucagon

24. The Cori Cycle Lactate and glucose shuttle between active muscle/RBC and liver (glucagon/insulin reg.) Liver gluconeogenesis buffers the blood glucose for use by muscle, RBC’s and brain (120 g/day) *Note: the brain fully oxidizes glucose, so it does not funnel back lactate GN 6 ATP 2 RBCs 2 ATP GL

25. The Alanine Cycle The liver can also use the amino acid Alanine similarly to Lactate Following transamination to pyruvate, gluconeogenesis allows the liver to convert it to glucose for secretion into the blood

26. Significance Remove lactate in muscle Increase blood sugar level using amino acids(alanine) in special situation

27. You should know: • Chemical steps of GN; associate enzymes • Requirement for mito shuttle system • Precursors that can enter GN; • Relationship of GL to GN; shared enzymes, irreversible steps • Liver as the primary GN organ; Cori Cycle, Alanine Cycle